tbuckley/cabot-search huggingface dataset:
NCOG-10. LONG-TERM SURVIVAL ANALYSIS OF PLEOMORPHIC XANTHOASTROCYTOMA: INSIGHTS INTO PROGNOSTIC FACTORS AND TREATMENT STRATEGIES
Authors: Chaejin Lee, Yukyeng Byeon, Gung-Ju Kim, Juhee Jeon, Young-Hoon Kim, Chang-Ki Hong, Jeong Hoon Kim, Sang Woo Song
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Pleomorphic xanthoastrocytoma (PXA) is rare, accounting for less than 1% of astrocytomas. Despite its pleomorphic histologic features, PXA generally carries a favorable prognosis. Limited research exists regarding the clinical course and treatment outcomes of PXA. This study aimed to identify prognostic factors and evaluate treatment strategies in PXA. METHODS We retrospectively analyzed PXA patients who underwent surgical resection at our institution from 2000 to 2021. Demographic data, radiologic characteristics, and treatment outcomes were collected. Tumors were classified as grade 2 or grade 3 based on the 2021 World Health Organization criteria. RESULTS Among the included patients, 40 were diagnosed with grade 2 PXA, while 9 had grade 3 PXA. Five-year progression-free survival (PFS) rates were 75.8% for grade 2 and 37.0% for grade 3 (p = 0.003). Multivariate Cox regression analysis revealed that both grade (p = 0.044) and tumor infiltration (p = 0.008) significantly influenced PFS. Factors such as hydrocephalus (p = 0.005) and tumor infiltration (p = 0.017) were found to affect overall survival (OS). Subgroup analysis in grade 2 PXA showed significantly better OS and PFS when gross total resection (GTR) was performed during the initial surgery, as opposed to subtotal resection (STR). Adjuvant radiation therapy did not significantly alter the prognosis of grade 2 PXA. CONCLUSIONS Tumor infiltration was associated with improved PFS and OS in grade 2 and 3 PXA cases. GTR had a significant positive impact on PFS in the overall group, and both PFS and OS in grade 2 PXA. Adjuvant radiation therapy did not significantly alter the prognosis of grade 2 PXA.
EXTH-04. CYTOSTATIC HYPOTHERMIA AGAINST GLIOBLASTOMA AND THE DEVELOPMENT OF A NEURAL IMPLANT FOR RODENTS AND SWINE
Authors: Syed Faaiz Enam, Reed Chen, Mahabad Barwari, Aksharkumar Dobariya, Ankur Patel, Toral Patel, Ravi Bellamkonda
Journal: Neuro-Oncology (2023)

Abstract Survival rates for patients with glioblastoma (GBM) remain discouraging due to the near-impossibility of eradicating all tumor cells, resulting in frequent recurrence. However, studies have shown that recurrence is predominantly localized (80% of cases) and that survival outcomes are improved with supra-total resection. Consequently, non-destructive local therapies hold promise for preventing GBM recurrence. We have demonstrated that non-freezing, 'cytostatic' hypothermia is a unique and effective approach against GBM. Unlike ablative cryogenic hypothermia, which kills both neoplastic and healthy infiltrated tissue, this method safely and effectively inhibits GBM growth. Through extensive investigations, we have previously identified a cytostatic window of 20–25°C and examined its impact on multiple pathways. By implementing hypothermia, we successfully inhibited GBM growth, doubling median survival in two rodent models. Notably, all rats subjected to cytostatic hypothermia survived the study period. To further advance towards translation, we conducted computer simulations to demonstrate the feasibility of a scaled and implantable system. Subsequently, we designed and fabricated a multiprobe array capable of uniformly extracting heat from a small volume of brain tissue in swine. This heat would then be transferred to the dorsal flank through an innovative artificial internal circulation system (AICS). The system underwent iterative testing in vitro and validation in vivo using live, anesthetized swine. Unlike targeted therapeutics that often show promise in preclinical models but fail in clinical trials, cytostatic hypothermia capitalizes on fundamental physics that broadly influence biology. It has the potential to reduce brain tumor recurrence, limit tumor evolution, and simultaneously offer time to patients as other cytotoxic therapies are developed.
EXTH-26. 3D LIVE MICROSCOPY AND SINGLE CELL TRANSCRIPTOMIC TO DECIPHER MOLECULAR ACTORS INVOLVED IN GLIOBLASTOMA CELL INVASION IN HUMAN CEREBRAL ORGANOIDS
Authors: Maite Verreault, David Akbar, Emeline Cherchame, Benjamin Galet, Emie Quissac, Philippe Ravassard, Ahmed Idbaih
Journal: Neuro-Oncology (2023)

Abstract Glioblastomas are characterized by a highly invasive phenotype involving heterogeneous and dynamic molecular effectors. This process is one of the first causes of relapse following standard treatment. In vitro 2D cell migration assays do not recapitulate the biological and cellular microenvironment present in the human brain. Here, human induced pluripotent stem cells (hiPSC) -derived ventral forebrain organoids (hVFO) were used to assess the invasion phenotype of a panel of glioblastoma patient-derived cell lines (PDCLs) from mesenchymal, proneural and classical molecular subtypes. 3D live confocal microscopy allowed to characterize invasion phenotypes between PDCLs. A wide diversity of invasion phenotypes was observed which could not be explained by molecular subtypes. Single cell transcriptomic analysis was performed on a highly invasive PDCL following hVFO invasion, which permitted the identification of putative molecular candidates involved in invasion processes. Functional validation of druggable candidates is ongoing and will be presented.
RBIO-08. GTP SIGNALING LINKS ALTERED METABOLISM, DNA REPAIR AND TREATMENT RESISTANCE IN GLIOBLASTOMA
Authors: Weihua Zhou, Zitong Zhao, Angelica Lin, John Yang, Jie Xu, Kari Wilder-Romans, Annabel Yang, Jing Li, Sumeet Solanki, Jennifer Speth, Natalie Walker, Andrew J Scott, Ayesha Kothari, Yangyang Yao, Erik Peterson, Navyateja Korimerla, Christian Werner, Jessica Liang, Janna Jacobson, Sravya Palavalasa, Alexandra Obrien, Ameer Elaimy, Sean Ferris, Shuang Zhao, Jann Sarkaria, Balázs Győrffy, Shuqun Zhang, Wajd Al-Holou, Yoshie Umemura, Meredith Morgan, Theodore Lawrence, Costas Lyssiotis, Marc Peters-Golden, Yatrik Shah, Daniel Wahl
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE We sought to define the mechanisms by which purines regulate DNA repair and therapy response. METHODS Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after radiation (RT) and antibodies generated against novel sites. Animal models of glioblastoma (GBM) and normal tissues were used to assess DNA repair and treatment responses in vivo. RESULTS Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT by inhibiting the activity of non-homologous end joining, but not homologous recombination. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced double-strand break (DSB) repair, and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to G protein Rac1. Expression of constitutively active Rac1 promoted but dominant negative Rac1 blocked the dephosphorylation of Abi-1 (S323) and DSB repair. Knock-down or inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. In GBM PDX samples, p-Abi-1 (S323) levels negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibiting Rac1 enhanced RT responses and suppressed Abi-1 (S323) dephosphorylation. Abi-1 knockout enhanced efficacy of genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in non-malignant cells and protected mice from RT-mediated gastrointestinal injury and bleomycin-induced pulmonary fibrosis. CONCLUSION The GTP-Rac1-PP5-Abi-1 signaling axis links metabolism and DNA repair. Disrupting this pathway can overcome GBM resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues.
CTIM-12. IMMUNOGENICITY OF AN ADDITIONAL DOSE OF COVID-19 VACCINE IN FULLY VACCINATED PATIENTS WITH GLIOMA TO EVALUATE NEW NATIONAL VACCINATION GUIDELINES - A PROSPECTIVE COHORT STUDY
Authors: Teresa Schmidt, Hana Rohn, Mirko Trilling, Sarina Agkatsev, Christoph Oster, Christoph Kleinschnitz, Ulrich Sure, Martin Stuschke, Björn Scheffler, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract Patients diagnosed with glioma belong to a high-risk group during the COVID-19 pandemic. These patients have a compromised immune function due to the malignancy itself, specific anticancer therapies such as temozolomide and symptom-alleviating corticosteroid treatments. While earlier studies have reported successful seroconversion after SARS-CoV-2 immunization in oncological patients, inclusive of those with glioma, the resulting antibody titers remain markedly inferior compared to the healthy population. The recent modification of COVID-19 vaccine guidelines in Germany advocates an additional annual vaccination for glioma patients. Our prospective cohort study endeavors to delineate the immunogenicity in fully immunized glioma patients through assessment of humoral and adaptive immune response post-administration of the supplementary vaccine dose. In this single-center study, glioma patients undergoing tumor-specific therapy will receive an adjunctive dose of the COVID-19 vaccine in conjunction with the seasonal influenza vaccine. A cohort of 70 glioma patients is planned for inclusion, and a comparative analysis will be conducted against a control group consisting of healthy relatives and healthcare professionals. Blood samples will be procured at two distinct intervals: T1, preceding the extra vaccine administration, and T2, 28 days following vaccination. Immunogenicity will be assessed by quantifying anti-SARS-CoV-2 spike (S) protein and nucleocapsid protein (N) concentrations and T-cell responses ascertained using the ELISPOT assay and flow cytometry. In parallel, a comprehensive evaluation of clinical data relevant to therapeutic interventions and corticosteroid usage will be undertaken. At the time of abstract submission, patient recruitment is in progress. Preliminary immunological and clinical data from this investigation, which seek to appraise immune competence and ascertain the clinical implications of the revised COVID-19 vaccination guidelines in glioma patients, will be presented.
INNV-13. PREDICTION OF MGMT METHYLATION FOR GLIOBLASTOMAS USING AI MODELS. A COST-EFFECTIVE FRAMEWORK FOR LOW AND MIDDLE-INCOME COUNTRIES
Authors: Felipe Restini, Fernanda Hayashida Yoshimoto, Leticia Hernandes de Brito, José Eduardo Vaz Nascimento, Anselmo Mancini, Cecilia Feliz Penido Mendes de Sousa, Maria Thereza Mansur Starling, Samir Abdallah Hanna, Gustavo Nader Marta, Wellington Furtado Pimenta Neves Junior
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND MGMT methylation (MGMTmet) is prognostic and predictive for patients with glioblastoma (GBM). However, financial constraints limit access to molecular tests, especially in low and middle-income countries. Artificial intelligence (AI) tools have emerged as a potentially cost-effective solution for identifying MGMTmet. Therefore, we are investigating if an AI model could select those at higher risk to present positive results for molecular confirmation, thus making a better resource allocation. METHODS We have selected GBM patients from the public image bank, The Cancer Imaging Archive, and we included all patients with a molecular evaluation of MGMTmet. We defined our volume of interest based on the ESTRO-ACROP 2016 guideline for GBM radiotherapy contouring and then extracted the radiomic features. The collected features underwent structured analysis, and a prediction model for MGMTmet was developed. We used a Random Forest algorithm to identify the most relevant features. Subsequently, the dataset was divided into training and validation sets. RESULTS We examined 100 patients with histologically classified high-grade gliomas and wild-type IDH, Sixty-one were unmethylated, and 39 were methylated. In this cohort, over 39,000 features were extracted. To avoid noise and overfitting, the 13 most predictive features were selected. They belong to the following feature classes: demographic, first order, Gray Level Size Zone Matrix, and Gray Level Co-occurrence Matrix. The preliminary model achieved an accuracy of 80% for predicting MGMTmet. CONCLUSION our preliminary results show a promising role for AI models in screening patients for molecular testing. This initiative demonstrates the utilization of research to bridge the public health gap. By sharing experiences and fostering collaboration, physicians can work towards mitigating healthcare inequalities in low-middle-income countries. In our future perspectives, we plan to enhance the algorithm's efficacy by incorporating qualitative human-generated features and expanding our sample size.
RBIO-03. BENEFICIAL CLOSTRIDIUM SPP ORAL SUPPLEMENTATION MITIGATES RADIATION-INDUCED COGNITIVE DYSFUNCTION WITH GUT MICROBIOTA MODULATION IN RICD MICE
Authors: Mahesh Bekal, Tushar Das, Maria P Blasco-Conesa, Gayathri Jagadeesan, Leomar Ballester, Bhanu Priya Ganesh, Yoshua Esquenazi
Journal: Neuro-Oncology (2023)

Abstract Radiation therapy (RT) a critical treatment for brain tumors; often leads to radiation-induced cognitive dysfunction (RICD), which significantly impacts patients' quality of life. The gut microbiome and its metabolites play a crucial role in regulating CNS function, RT disturbs the balance of the gut microbiota causing dysbiosis (imbalance in beneficial microorganisms), and Gut-dysbiosis have been linked to various cognitive disorders. This study aims to investigate the effects of RT on the gut-microbiome and cognitive function, C57BL/6 mice were exposed to Sham/9Gy/15Gy cranial irradiation and conducted cognitive tests using the Y-maze and Novel Object Recognition Test at different time points. Both 9Gy and 15Gy irradiation led to significant cognitive dysfunction at 10 and 30 days post-irradiation. We collected fecal samples before RT and at 10 and 30 days after RT to extract microbial DNA. The 16S rRNA gene was sequenced and analyzed using the ATIMA visualization toolkit. By comparing pre-irradiation samples with samples at 10 and 30 days post-irradiation, we observed significant gut dysbiosis in both 9Gy and 15Gy irradiated mice. The 15Gy group exhibited more pronounced and consistent changes in fecal microbiome diversity following RT. Notably, the Clostridium group at the order, family, and genus levels consistently decreased in the 15Gy irradiated mice. Certain Clostridium species are known as major producers of Short Chain Fatty Acids (SCFAs) in the gut. Based on this, we hypothesized that oral supplementation with beneficial SCFA-producing bacteria could ameliorate RICD. To test this hypothesis, a separate group of mice received 15Gy RT along with oral gavage containing a cocktail of Clostridium strains. After a 20-day post-irradiation, cognitive tests revealed that the group supplemented with Clostridium spp exhibited significantly improved cognitive performance. Our findings suggest that gut dysbiosis may contribute to RICD, and oral supplementation of SCFA-producing bacteria could be a potential strategy to mitigate RICD.
EXTH-37. FUNCTIONAL GENOMICS IDENTIFIES THERAPEUTIC VULNERABILITIES OF GLIOMA SUBTYPES AND YAP/TAZ-ENRICHED TUMORS
Authors: Wan-Hsin Lin, Farhad Kosari, James Smadbeck, Michael Barrett, Ryan Feathers, Alan Penheiter, Jamie Lynch, Sotiris Sotiriou, Dorsay Sadeghian, Vijaya Kadam Maruthi, Sarah Johnson, Giannoula Karagouga, Faye Harris, Taylor Berry, Alexa McCune, Stephen Murphy, Lindsey Kinsella, Diogo Moniz-Garcia, Shannon Fortin Ensign, Lin Yang, Angela Emanuel, Rebecca Salvatori, Janet Schaefer Klein, Cristine Ida, Mark Jentoft, Marcela Salomao, Wendy Sherman, Alyx Porter, Steven Rosenfeld, Sani H Kizilbash, Kurt Jaeckle, Maciej Mrugala, Aaron Mansfield, Mitesh Borad, Bernard Bendok, Terry Burns, Alfredo Quiñones-Hinojosa, John Cheville, George Vasmatzis, Panos Anastasiadis
Journal: Neuro-Oncology (2023)

Abstract Sequencing efforts have identified key oncogenic drivers and transcriptomic subtypes of high-grade gliomas (HGGs), but this knowledge has not resulted in individualized therapy or improved patient outcomes. Here, we used a functional genomics approach combining integrated genomic/transcriptomic analyses with patient-derived 3D micro-cancers (mCancers) to rapidly identify individualized therapeutic vulnerabilities and determine predictive response biomarkers. 30 primary/recurrent HGGs, including 20 glioblastomas, 5 astrocytomas, and 5 oligodendrogliomas, were included for drug testing. mCancers recapitulated the structural and molecular alterations, cellularity, and heterogeneity, of parental patient tumors. A total of 119 single-agent drugs and 183 drug combinations were tested, while a pre-selected drug panel comprising 25 glioma-relevant treatment strategies was tested across all cases. In general, mCancer efficacy corresponded well to historical responses to previously tested agents (EGFR, HDAC inhibitors, etc.). Combined, strong efficacy (i.e. &amp;gt;70% growth inhibition at Cmax) of single treatments targeting deregulated receptor tyrosine kinase (RTK), p53/apoptosis, cell cycle, DNA damage repair, IDH, or telomere maintainance pathways, was observed in 14 out of 30 cases. Surprisingly, transcriptional signatures, but not specific genetic alterations, were found to stratify drug responses. For example, mCancers enriched for the most aggressive mesenchymal (MES) and glycolytic/plurimetabolic (GPM) transcriptional subtypes exhibited stronger response to the BET inhibitor JQ1 (and other clinical BET inhibitors) and the DNA-PKcs/mTOR dual inhibitor CC-115. This therapeutic vulnerability was associated with enrichment of YAP/TAZ signaling, and the glioblastoma stem cell G-STEM signature. Notably, individual combination strategies were effective across tumors, with strong responses ranging from 38% to 77% of all tumors tested. Overall, this study underscores the value of functional genomics in identifying novel vulnerabilities of HGGs and associated response biomarkers. It also highlights the need for further clinical validation of several novel therapies and especially drug combination strategies with strong efficacy in the ex vivo setting.
BIOM-61. EXPLORING HOMOLOGOUS RECOMBINATION DEFICIENCY IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Ke Xu, Evan Savage, Jason Myers, Evadnie Rampersaud, Yawei Hui, Ti-Cheng Chang, Gang Wu, Christopher Tinkle, Anang Shelat
Journal: Neuro-Oncology (2023)

Abstract Homologous recombination deficiency (HRD) has been extensively studied in breast cancer and ovarian cancer given its correlation with sensitivity to Poly (ADP-ribose) polymerases (PARP) inhibitors. In these cancers, HRD is most frequently caused by biallelic inactivation of BRCA1/2 and tumors often exhibit ‘genomic scars’ such as elevated HRD.sum score and specific mutational signatures, including specific single nucleotide variant (SNV), small insertion/deletion (Indel), and structural variant (SV) signatures. Despite its clinical relevance, HRD has not been systematically studied in pediatric cancers and its therapeutic predictive value is unknown. Here, we evaluated HRD in 255 tumor-normal paired whole-genome-sequenced (WGS) samples of pediatric high-grade glioma (pHGG) and 23 tumor-normal paired WGS samples of breast cancer (BC) as comparison. We found that 9% of the pHGG samples have HRD.sum score greater than 40, an indicator of HRD in several adult cancers. However, while we identified HRD-related SNV signature SBS3 and SV signature RS5 in some of the pHGG samples, HRD-related Indel signature ID6 was not identified. We also evaluated two composite scores, namely, HRDetect and CHORD, on our samples. While virtually all BC samples with BRCA1/2 loss were predicted to be HRD by both scores, none of the pHGG samples was predicted to be HRD by either score. We profiled somatic and germline variants from over 500 DNA damage response genes in the pHGG samples and identified TP53 as the most frequently mutated genes with biallelic loss, whereas biallelic loss of BRCA1/2 was not found. Overall, our study suggests that HRD exists in a fraction of pHGG samples, but is driven by inactivation of genes other than BRCA1/2, resulting in a different set of genomic scars compared to those in BCs. Functional analysis of sensitivity to PARP inhibitor and related DNA damage inhibitors is ongoing to evaluate potential therapeutic relevance of these genomic scars.
NCOG-15. COMPARATIVE ANALYSIS OF GLIOMA INDUCED IMPAIRMENT MODELS
Authors: Jasleen Kaur, Alexander Aabedi, Kirsti Brandes, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2023)

Abstract Speech is produced by the coordination of neural networks involved in language processing and motor control of vocal outputs, both of which can be disrupted by diffuse gliomas. Natural language is the instinctual written or spoken language profile that an individual has developed throughout his or her lifetime. Recent psycholinguistic analyses suggest that patterns of natural language may be an accurate measure for assessing clinical and behavioral conditions. One important feature of natural language is speech onset. Speech delays are common complaints among patients with glioma. Here, we assess the relationship between speech onset and histologic-molecular features of glioma. Speech onset was defined as acoustic measure of the interval of time between the release of the oral constriction in a stop consonant and the onset of subsequent voicing. Audio samples and video analysis of oral kinetics were analyzed from patients with newly diagnosed low- and high-grade glioma. Features were extracted by manual segmentation and aligned for each trial with high-density electrode arrays to record task specific responses from gliomas projecting to the cortical surface. A total of 1,120 stimuli (672 = picture naming (PN) and 448 auditory naming (AN) trials were presented. As expected, patients with glioblastoma had higher picture and auditory naming error rates (p &amp;lt; 0.001, Mann-Whitney U test) compared with diffuse low-grade gliomas. Assuming speech errors produce slower response times, we next measured only correct behavioral responses which demonstrated 7% slower speech initiation responses (p &amp;lt; 0.0001, Mann-Whitney U test) when comparing patients with glioblastoma and diffuse low-grade gliomas. Slowed speech responses did not require glioma infiltration into canonical cortical speech areas of the lateral prefrontal cortex and superior temporal gyrus. Finally, we identified electrophysiological biomarkers of speech errors. These results deepen our understanding of speech processing impairments, which are not based purely on coding errors.